Nu, nu&#39;-substituted diurethanes



Patented June 22, 1954 N,N'-SUBSTITUTED DIURETHANES Norman Rabjohn, Columbia, Mo., assignor to Curators of the University of Missouri, Columbia, Mo., a public corporation of the State of Missouri No Drawing. Application August 20, 1951, Serial No. 242,793

8 Claims.

This invention relates to novel chemical com-- pounds and to methods of preparing the same, and, more particularly, it relates to N,N'-substituted diurethans possessing properties making them especially valuable as pharmaceutical agents.

Procaine, also known as novocaine, (2-diethylaminoethyl p-aminobenzoate) and modifled or substituted procaines have proven to be very valuable pharmaceutical agents and have been used widely as anesthetics. However, as is well known, such compounds, as well as other well-known anesthetics, possess certain undesirable properties, especially when administered to sensitive individuals. For example, they produce vasodilatation and stimulate the nervous system, resulting in hyperirritability, restlessness, tremors, and, in lethal doses, eventual death by convulsions. Such undesirable properties are particularly marked in cases of massive infiltration and in the relatively new use of the compounds intravenously.

One object of the present invention is to provide new chemical compounds of advantageous properties.

A further object of the invention is to provide pharmaceutical agents of high anesthetic potency but which, when administered, especially when injected intraperitoneally, will not produce vasodilatation or excitation.

Still another object of the invention is to provide novel anesthetic compounds, which, while possessing the advantageous properties of procaine and similar compounds, will be free from their undesirable characteristics, for example, will lack the undesirable central nervous stimula tion properties which are common to procaine and other well-known anesthetics.

Still another object of the invention is to provide an economical method by which the novel compounds of the invention may be prepared.

Other objects will be apparent from a consideration of this specification and the claims.

As stated, the compounds of the present 'invention are N,N'-substituted diurethans and, therefore, contain the characteristic diurethan structure:

More specifically, the compounds of the present invention have the following fundamental structural formula:

where X is selected from the group consisting of a saturated straight hydrocarbon chain containing from two to ten carbon atoms; a saturated branched hydrocarbon chain containing from 3 to 10 carbon atoms, an unsaturated hydrocarbon chain containing from four to ten carbon atoms, a phenylene group, a cyclohexylene group, and an ether linkage -R'-OR where R. is selected from the group consisting of ethylene, trimethylene, and propylene; where R is selected from the group consisting of hydrogen or an alkyl group containing from one to four carbon atoms; where R1 is selected from the group consisting of hydrogen, an alkyl group containing from one to four carbon atoms and an alkoxy group containing from one to four carbon atoms; where R2 is selected from the group consisting of hydrogen and an alkyl grou containing from one to three carbon atoms; where R: is an alkyl group containing from one to four carbon atoms; and where R4 is an alkyl group containing from one to four carbon atoms.

Referring further to X, when X is a saturated or unsaturated hydrocarbon chain, the group may be straight or branched chain. Typical examples of saturated straight hydrocarbon chains which may be present are ethylene, (CHz)2-; trimethylene, -(CH2)3-; tetramethylene,

pentamethylene, (CI-I2)5; hexamethylene, (CH2) r; and decamethylene, (CI-I2) 10. Typical examples of saturated, branched hydrocarbon chains which may be present are: propylene, CI-l(CI-Is)CH2-; 2-methyl trimethylene,

' CH2CH(CH3) CH2" 1 methyl trimethylene, CH(CH3)CH2CH2;

and 3,3, dimethyl pentamethylene,

(CH2)2C(CH3)2(CH2)2 When X is an unsaturated hydrocarbon chain, it may contain a double bond or a triple bond, typical examples being: Z-butenylene,

CH: CH:

3 Referring to R, R1, R2, R3, and R4, when these groups are alkyl groups, the hydrocarbon chain may be straight or branched, examples being methyl, ethyl, n-propyl, isopropyl, and, in the case of R, R1, R3, and R4, n-butyl, iso-butyl, and sec-butyl, and Where R1 is an alkoxy group, the corresponding alkoxy groups maybe present,

When X is a phenylene group, the linkage of the N( l0 groups therewith may be ortho, meta, or para, preferably para. Likewise, when X is a cyclohexylene group, the linkage of the o N( to g oups th rewith may e ,2; or preflinkage may be located, with respect to the phenylene group there shown, at a position ortho, meta, or para to the carboxyl group, preferably at the para position, and the R group may be located at the ortho, meta, or para position, preI" erably at the ortho position.

The preferred compounds for use as anesthetics are those in which R, R1, and Rs are hydrogen, in which R3 and R4 are ethyl groups and in which the II I linkage in the structural formula is located, with respect to the phenylene group in the formula, at the para position. These preferred compounds, therefore, have the following fundamental structural formula:

where X is as above defined. It will be recognized that a, portion of the formula, namely,

atoms (CHzCI:Ir),th,e compound has the following fundamental structural formula and may be designated the diethylaminoethyl ester of. N,N di (p-carboxy phenyl) ethylene diurethan, and the other preferred compounds may be similarly designated by the-substitution of the appropriate designation ofthe saturated straight hydrocarbon. chain forethylene in the name-of the compound.

As is well-known, amines generally, including procaine and modified or substituted procaines,

are formed into salts by addition of an acid to nitrogen in the molecule. Z'hese procaine salts, as well as the bases, are employed as anesthetics. Hence, the various compounds within the scope of this invention may be prepared and used either as the base or the salt. In the molecule of the compounds of the present invention, there are two basic nitrogens (the nitrogens to which the alkyl groups (R3 and R4) are attached) to which acid may be added to form a salt. Thus, for example, the structural formula for the hydrochloride of the compounds of the present invention may be Written as follows:

In view of the fact that the salts differ only from the bases in the addition of the acid to the nitrogen atoms referred to, and are characterized by the same structural formula, the salts, as well as the bases, are included within the scope of this application and of the claim wherever reference is made to a compound comprising; a stated structural formula.

The acid forming the salt may be any inorganic or organic acid desired, for example, hydrochloric, hydrobrom-ic, hydroiodic, nitric, sulphuric, phosphoric, and the like; acetic and other acids of this series (for instance, propionic, caproic, stearic, and the like), crotonic, oleio, oxalic, citric, tartaric, lactic, benzoic, naphthoic, picric, salicylic, dili-turic, and the like. It will be understood that with certain acids, the salt, while existing solution and being usable as such may present difficulty in its isolation in solid form.

The compounds of the invention are readily prepared by condensing two mols of the appropriate aromatic aminobase or a saltthereof, both of which are included within the term aromatic amino. compound, for instance, procaine or procaine hydrochloride, with one mol of the appropriate dichlorocarbonate or dibromocarbonate.

L The fundamental structural formula of the arc-- inatic amino compound is, represented by:

NHR R4 and the formula for the dihalocarbonate may. be presented by where the various: Bis: and other relationships and X ar a heretofore defined in connection with the fundamental structural formula of the compounds of the invention and where Y'is selected fromthe group consisting of chlorine. or bromine.

The desired dichlorocarbonate or dibromocarbonate may be readily prepared by reacting, by

known procedures, theappropriate dihydroxy compound (glycol), of which X-- in theabove formula is the residue, with carbonyl chloride (phosgene) orcarbonyl bromide. Generally, the required amount of the glycol is added slowly to the liquid carbonyl halide cooled in an ice bath. After the reaction is complete, the excess ca-rbonyl halide is allowed to evaporate and theresidue is advantageously warmed to removetraces of the carbonyl halide and the corresponding hydrogen halide, Alternatively, the carbonyl halidemay be passed as a gaseous streaminto the glycol maintainedin anicebath and after the reaction, the excess carbonyl halide and the hydrogen chloride or bromide may be removed under reduced pressure.

In view of the fact that in preparing the compounds the use of a dichlorocarbonate is preferred, the invention will be described using such compound as the reactant but it is to be understood that if desired the dibromocarbonate may be used. The condensation of the dich1orocarbonate with the aromatic amino compound presents no problem because they are readily reactive and can be reacted directly, if desired. For manipulative reasons, however, it is desirable to conduct the reaction in the presence or a solvent such as water, acetone, alcohol, or mixtures thereof. Conventional chemical apparatus can be employed and it is usually desirable to add the aromatic amino compound, dissolved in a suitable solvent, into the reactor and to add the dichlorocarbonate dissolved in a suitable solvent from a dropping device. After the chemical reaction has subsided, the N,N'-substituted diurethan may be conveniently separated from the reaction mixture by removal of part or all of the solvent used during the reaction and filtration of the product if it is a solid. The diurethans which are liquids may be removed conveniently by extraction with a suitable solvent such as n-butanol or chloroform.

When the reaction is conducted in the absence of a basic material, the dihydrochloride salt of the compound i formed and the salt may then be treated with a basic material which will convert the salt into the base, that is, a basic material which is stronger than the N,N-substituted diurethan formed. In the event it is desired to form the base directly, the condensation is conducted in the presence of a relatively strong base, examples of which are sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, triethylamine, N-methyl piperidine, N-methyl morpholine, and any other basic material which will not enter into the reaction and which has a base strength greater than the base strength of the MDT-substituted diurethan formed, thus reacting with the hydrogen chloride. If such a basic material is employed, it may be added to the reactants in any desired manner, for example, it may be added gradually to the reaction mixture by means of a dropping device, in which event, it is desirable to add the dichlorocarbonate at a rate so that there is present in the reaction mixture a slight excess of the dichlorocarbonate over the basic material at all times.

The reaction may be illustrated by the following equations, in which ethylene dichlorocarbonate is reacted with procaine, it being understood that the hydrochloride may be used in place of the free base, if desired:

(a) In the presence of a strong base:

2NHz-O-O ologalmcznm 010 o o-oim-o o o 01 12MOH (b) In the absence of a strong base:

The free base of the compound, either as obtained directly from the reaction or from the dihydrochloride, can be converted into any desired salt by reacting the base with the appropriate acid by conventional procedures, for example, by simply mixing the base and the acid in a solvent, if desired.

The following examples serve to illustrate further the present invention:

Example I A solution of 5.45 g. (0.02 mol) of procaine hydrochloride, in 20 ml. of water, is warmed to 40, and 1.87 g. (0.01 mol) of ethylene dichlorocarbonate, in 10 ml. of acetone, is added slowly. When the addition is about one-half complete, the first drop of a 7 m1. quantity of triethylamine is added. The addition or" both reagents is controlled so that some free dichlorocarbonate is present at all times in the reaction mixture. After the addition of the triethylamine is completed, the mixture is warmed, with stirring, until the acetone is removed. The mixture is allowed to cool slow ly and is then cooled to 5 and filtered to give 5.52 g. (94%) of a white product; M. P., -130". This material is crystallized from a mixture of ethyl acetate and petroleum ether (B. P. 60-70") to yield 4.91 g. (85%) of the N,Ndisubstituted diurethan which melts at -141.

The compound is analyzed and is found to contain 61.18% C and 7.25% H. The formula for Following the same general procedure, the corresponding dimethylamino-, dipropylamino-, and

dibutylamino derivatives may be prepared.

Example II A solution of 33. 4 g. (0.122 mol) of procaine hydrochloride, in 200 ml. of acetone and 25 ml. of Water, is stirred \vhile 14.0 g. (0.061 mol) of pentarnethylene dichlorocarbonate is added dropwise. The solution turns cloudy rapidly and crystallization is complete within ten minutes after all of the dichlorocarbonate is introduced. The reaction mixture is cooled, filtered, and sucked as dry as possible. The white mass is dried in a vacuum oven at 65/20 mm. to give 42.5 g. (99%) of product. After crystallization from a mixture of alcohol and n-hexane, the N,N disubstituted diurethan dihydrochloride melts at 176-177".

The compound is analyzed and is found to corn tain 56.68% C and 7.30% H. The formula for the compound is:

Following the same general procedure, the salts of the corresponding dimethylaminoand diprcpylamino derivatives may be prepared.

Example III Using the procedure of Example 1, except that trimethylene dichlorocarbonate is employed as the reactant, an N,N'-disubstituted diurethan is obtained of the structural formula:

Example IV Using the procedure of- Example I, except that tetramethylene dichlorocarbonate is used as the reactant and acetone-is usedas the solvent for crystallization, an N,N-disubstituted diurethan is obtained having the structural formula:

CzHs The compound has. a melting point of 137-188" 0., and, upon analysis, 62.50% C and 7.51% H.

Example V Using theprocedure of Example I, except that pentamethylene dichlorocarbonate is employed as the reactant, an N,'N'-disubstituted diurethan is obtained having :the structural formula:

CzHsJ: The. compoundhas a melting point of l56-l57 C., and upon analysis, 63.10% C and 7.83% H.

Example VI Using theprocedure of Example 1, except that hexamethylene dichlorocarbonate is used as the reactant and alcohol is used as the solvent for crystallization, an N,N-disubstituted diurethan is obtained having the-structural formula:

The compound :hasxa melting point of 190-19? 0., and, upcnana'lysis, 63.33% C'and 7.74% H.

Example VII Using the procedure of Example I, except that decamethylene dichlorocarbonate is used as-the r actant andethyl acetateis used as the solvent for crystallization, an N,N-'disubstituted diurethan is obtained having the structural for mula:

The compound has a meltingpoint of ISO-161 0., and, upon analysis, 65.35% Can-d 8.50% H;

Example VIII Using the procedure of Example I, except that his 2,2'-oxydiethyl dichlorocarbonate is. used as the reactant and amixture of ether and petroleum ether- (B; P; 60-70'C.) is usedas the solvent for crystallization, an -N,N-disubstituted diurethanis obtained having the structural formula:

8 The compound has a meltingpoint of 122-123 C., and upon analysis, 60.65% C and 7.11% H.

Example IX Usingthe procedure of Example II, except that ethylene dichlorocarbonate is used as the reactant, an N,N-disubstituted diurethan dihydrochloride is obtained having the structural formula:

The compound has a'melting point of 199-200 (7., and, upon analysis, 54.93% C and 7.01% H.

Example X Using the procedure of Example II, except thattrimethylene dichlorocarbonate is used as the reactant and a mixture of alcohol-and acetoneis used as the solvent for crystallization, an N ,N disubstituted diurethan dihydrochloride is obtained having the structural formula:

The compound-has a melting'point of 170-171 and, upon analysis, 55.05% C and 7.17% H.

Example XI Using the procedure of- Example 11, except that tetramethylene dichlorocarbonate is used as the reactant and a mixture of alcohol and acetone is used as the solventfor crystallization,

an N,N-disubstituted diurethan dihydroohloride is obtained having the structuraLformula:

g H CzH; I

- ZHC] Cz s 2 The compound has amelting point of 205-206 0., and, upon analysis, 56;00% C and-7.21% H.

Example XII Using the procedure of Example II, except that 2-butynylene dichlorocarbonate is used as the reactant and a mixture of alcohol and ether is used as the solvent for crystallization, an N ,N- disubstituted diurethan dihydrochloride is obtained having the structural-formula:

O H C2115 The compound has a melting point of 18l-183 C., and, upon analysis, 56.35% C and 6.36% H.

Example XIII Using the procedure of Example I1; except that his 2,2-oxydiethyl dichlorocarbonate is used as the reactant and a mixture of methanol and ethyl acetate is used as the solvent for crystallization, an- N,N-disubstituted diurethan dihydrochloride is obtained having' the structural formula:

021-15 2 The compound has a melting point of 191192 C., and, upon analysis, 54.36% C and 7.18% H.

Example XIV Using the procedureof Example II, except (12H, that decamethylene dichlorocarbonate is used as aceipt t the reactant and water is used as the solvent for urethan dioxalate is obtained having the struc crystallization, an N,N-disubstituted diurethan tural formula: dihydrochloride is obtained having the structural CzHs 2 The compound has a melting point of The compound has a melting point of 115-117 C., and, upon analysis, 59.23% C and 8.11% H. 10 0., and, after analysis, 54.69% C and 6.46% H.

Following an analogous procedure, the disali- Example XV cylic and didilituric acid salts of the correspond- Using the procedure of Example 11, except ing tetramethylene derivative (i. e. tetrameththat 1,4 cyclohexylene dichlorocarbonate is used y ene i tead of 2 yl trimethylene in the as the reactant and a mixture of methanol and above formula) are prepared. The disalicylate acetone is used as the solvent for crystallization, is a white powder having a melting point of an N,N-disubstituted diurethan dihydrochloride 1405-1415 C., and the didiliturate has a melting is obtained having the structural formula: point of 235-236 C.

CHz-CHz @2115 2 The compound has a melting point of 213-21 C., and, upon analysis, 57.01% C and 6.77% H.

Example XVI Using the procedure of Example II, except that p-phenylene dichlorocarbonate is used as the reactant and a mixture of alcohol and ether is Example- XIX Following the procedure of Example XVII, except that l-methyl trimethylene dichlorocarbonate is used as the reactant, an N ,N-disubstitutecl diurethan dioxalate is obtained having the structural formula:

used as the solvent for crystallization, an N,N- f /O2H5 disubstituted diurethan dihydrochloride is ob- -OH-OHz-CH2- -O(JJ-NOCO2C2H4N amozo. tained having the structural formula: CH5 2 R F /GZH5 The compound has a melting point of 162- OCNOCO2C2H4N\ 22101 164 0., and, upon analysis, 54.33% C and 6.30%

2 5 I Example. XX The compound has a melting point of 164-166" 0., and, upon analysis, 57.60% C and 6.21% H, Following the procedure of Example XVII, except that 3,3-dimethyl pentamethylene dichloro- Example XVII 4O carbonate is used as the reactant and alcohol is Following the procedure of Example I, except used as the solvent for crystallization of the salt, that propylene dichlorocarbonate is used as the an l\T,N'-disubstituted diurethan dioxalate is obreactant, an oily material is obtained. After tained having the formula:

extraction with a mixture of n-butanol and chlo- The compound has a melting point of 150-152 roform and removal of the solvent, the base is C., and, upon analysis, 55.86% C and 6.70% 1-1. converted to the dioxalate salt which is crystallized from a mixture of methanol and ether. The

Z salt has the structural formula: Ewamp e XXI 1 Following the procedure of Example XVII, ex-

on; 02135 2 ate is used as the reactant and the dipicrate salt The compound ha melting point, of 112414 is formed, an N,N-disubstituted diurethan is ob- C., and, upon analysis, 53.54% C and 6.50% H. tained having the structural formula:

Example XVIII Following the procedure of Example XVII, except that Z-methyl trimethylene dichlorocar- EmmPZe'XXH bonate is used as the reactant and a mixture of Following the procedure of Example XVII, exalcohol and ether is used as the solvent for cryscept that l-methyl trimethylene dichlorocartallization of the salt, an N,N'-disubstituted dibonate is used as the reactant and the dipicrate 70 The compound has a melting point of -131 C., and, upon analysis, 49.00% C and 4.79% H.

The compound has a melting point of 144-145" 10 0., and, upon analysis, 49.51% C and 5.19% H.

Example XXIII A solution of ml. of water and ml. of acetone, containing 1.28 g. (0.004 mol) of 2-diethylaminoethyl o-methoxy-p-aminobenzoate is prepared. To this solution is added 0.240 g. (0.002 mol) of tetramethylene dichlorocarbonate. The mixture is allowed to stand for three days and 0.21 g. (.002 mol) of triethylamine is then added. The mixture is warmed on a steam bath until all of the acetone is removed, after which 10 m1. of water is added. This mixture is then extracted with chloroform, the organic layer dried and the solvent removed. The residual oil is dissolved in ether and the solution is saturated with dry hydrogen chloride. The white solid which is obtained in good yield is collected and crystallized from a mixture of methanol, ethyl acetate and ether.

The product has the structural formula:

OCH:

The compound has a melting point of 148-150 C., and, upon analysis, 54.69% C and 7.28% H.

Compounds formed by reaction of the dichlorocarbonates with 2-diethylaminoethyl o-isopropyl-p-aminobenzoate; Z-diethylaminoethyl o-butoXy-p-aminobenzoate, and their salts, are also prepared in the same general manner.

Example XXIV To 13 g. (0.04 mol) of crude 2-diethylamino-lmethylethyl p-aminobenzoate in alcohol is added 4.7 g. (0.02 mol) of tetramethylene dichlorocarbonate. The mixture is heated to remove the excess alcohol and upon cooling 6 g. of a crystalline product is obtained. After crystallization from alcohol, the diurethan dihydrochloride:

. 12 ticular techniques employed in preparing the compounds without departing from the scope of the invention.

I claim:

1. N,N disubstituted diurethans comprising the structure:

Q0 oiozmmoimiil 2 where n is a number from two to ten.

3. N,N disubstituted diurethans comprising the structure:

1-omon1m o=mn1 where n is a number from two to six.

4. An N,N-disubstituted diurethan comprising the structure:

5. An N,l I-disubstituted diurethan comprising 6. An N,N-disubstituted diurethan comprising the structure:

7. An N,N-disubstituted diurethan comprising the structure:

8. An N ,Ndisubstituted diurethan comprising the structure:

No references cited. 

1. N,N'' - DISUBSTITUTED DIURETHANS COMPRISING THE STRUCTURE: 